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排序方式: 共有142条查询结果,搜索用时 15 毫秒
1.
Shimamura T Shiroishi M Weyand S Tsujimoto H Winter G Katritch V Abagyan R Cherezov V Liu W Han GW Kobayashi T Stevens RC Iwata S 《Nature》2011,475(7354):65-70
The biogenic amine histamine is an important pharmacological mediator involved in pathophysiological processes such as allergies and inflammations. Histamine H(1) receptor (H(1)R) antagonists are very effective drugs alleviating the symptoms of allergic reactions. Here we show the crystal structure of the H(1)R complex with doxepin, a first-generation H(1)R antagonist. Doxepin sits deep in the ligand-binding pocket and directly interacts with Trp?428(6.48), a highly conserved key residue in G-protein-coupled-receptor activation. This well-conserved pocket with mostly hydrophobic nature contributes to the low selectivity of the first-generation compounds. The pocket is associated with an anion-binding region occupied by a phosphate ion. Docking of various second-generation H(1)R antagonists reveals that the unique carboxyl group present in this class of compounds interacts with Lys?191(5.39) and/or Lys?179(ECL2), both of which form part of the anion-binding region. This region is not conserved in other aminergic receptors, demonstrating how minor differences in receptors lead to pronounced selectivity differences with small molecules. Our study sheds light on the molecular basis of H(1)R antagonist specificity against H(1)R. 相似文献
2.
3.
Thibault ST Singer MA Miyazaki WY Milash B Dompe NA Singh CM Buchholz R Demsky M Fawcett R Francis-Lang HL Ryner L Cheung LM Chong A Erickson C Fisher WW Greer K Hartouni SR Howie E Jakkula L Joo D Killpack K Laufer A Mazzotta J Smith RD Stevens LM Stuber C Tan LR Ventura R Woo A Zakrajsek I Zhao L Chen F Swimmer C Kopczynski C Duyk G Winberg ML Margolis J 《Nature genetics》2004,36(3):283-287
With the availability of complete genome sequence for Drosophila melanogaster, one of the next strategic goals for fly researchers is a complete gene knockout collection. The P-element transposon, the workhorse of D. melanogaster molecular genetics, has a pronounced nonrandom insertion spectrum. It has been estimated that 87% saturation of the approximately 13,500-gene complement of D. melanogaster might require generating and analyzing up to 150,000 insertions. We describe specific improvements to the lepidopteran transposon piggyBac and the P element that enabled us to tag and disrupt genes in D. melanogaster more efficiently. We generated over 29,000 inserts resulting in 53% gene saturation and a more diverse collection of phenotypically stronger insertional alleles. We found that piggyBac has distinct global and local gene-tagging behavior from that of P elements. Notably, piggyBac excisions from the germ line are nearly always precise, piggyBac does not share chromosomal hotspots associated with P and piggyBac is more effective at gene disruption because it lacks the P bias for insertion in 5' regulatory sequences. 相似文献
4.
Synapses recycle their spent vesicles in order to keep up with on-going neurotransmitter release. To investigate vesicle recycling in the small synapses of hippocampal neurons, we have used an optical recording method that permits us to resolve single-vesicle events. Here we show that an exocytic event can terminate with three modes of vesicle retrieval: a fast (400-860 ms) 'kiss-and-run' mode that has a selective fusion pore; a slow (8-21 s) 'compensatory' mode; and a 'stranded' mode of recycling, in which a vesicle is left on the cell surface until a nerve impulse triggers its retrieval. We have also observed that, in response to a nerve impulse, synapses with low release probability primarily use the kiss-and-run mode, whereas high release probability terminals predominantly use the compensatory mode of vesicle retrieval. 相似文献
5.
Immunoglobulin light chains are the precursor proteins for fibrils that are formed during primary amyloidosis and in amyloidosis associated with multiple myeloma. As found for the approximately 20 currently described forms of focal, localized, or systemic amyloidoses, light chain-related fibrils extracted from physiological deposits are invariably associated with glycosaminoglycans, predominantly heparan sulfate. Other amyloid-related proteins are either structurally normal, such as beta2-microglobulin and islet amyloid polypeptide, fragments of normal proteins such as serum amyloid A protein or the precursor protein of the beta peptide involved in Alzheimer's disease, or are inherited forms of single amino acid variants of a normal protein such as found in the familial forms of amyloid associated with transthyretin. In contrast, the primary structures of light chains involved in fibril formation exhibit extensive mutational diversity rendering some proteins highly amyloidogenic and others non-pathological. The interactions between light chains and glycosaminoglycans are also affected by amino acid variation and may influence the clinical course of disease by enhancing fibril stability and contributing to resistance to protease degradation. Relatively little is currently known about the mechanisms by which glycosaminoglycans interact with light chains and light-chain fibrils. It is probable that future studies of this uniquely diverse family of proteins will continue to shed light on the processes of amyloidosis, and contribute as well to a greater understanding of the normal physiological roles of glycosaminoglycans. 相似文献
6.
Complete genome sequence of a multiple drug resistant Salmonella enterica serovar Typhi CT18. 总被引:33,自引:0,他引:33
J Parkhill G Dougan K D James N R Thomson D Pickard J Wain C Churcher K L Mungall S D Bentley M T Holden M Sebaihia S Baker D Basham K Brooks T Chillingworth P Connerton A Cronin P Davis R M Davies L Dowd N White J Farrar T Feltwell N Hamlin A Haque T T Hien S Holroyd K Jagels A Krogh T S Larsen S Leather S Moule P O'Gaora C Parry M Quail K Rutherford M Simmonds J Skelton K Stevens S Whitehead B G Barrell 《Nature》2001,413(6858):848-852
Salmonella enterica serovar Typhi (S. typhi) is the aetiological agent of typhoid fever, a serious invasive bacterial disease of humans with an annual global burden of approximately 16 million cases, leading to 600,000 fatalities. Many S. enterica serovars actively invade the mucosal surface of the intestine but are normally contained in healthy individuals by the local immune defence mechanisms. However, S. typhi has evolved the ability to spread to the deeper tissues of humans, including liver, spleen and bone marrow. Here we have sequenced the 4,809,037-base pair (bp) genome of a S. typhi (CT18) that is resistant to multiple drugs, revealing the presence of hundreds of insertions and deletions compared with the Escherichia coli genome, ranging in size from single genes to large islands. Notably, the genome sequence identifies over two hundred pseudogenes, several corresponding to genes that are known to contribute to virulence in Salmonella typhimurium. This genetic degradation may contribute to the human-restricted host range for S. typhi. CT18 harbours a 218,150-bp multiple-drug-resistance incH1 plasmid (pHCM1), and a 106,516-bp cryptic plasmid (pHCM2), which shows recent common ancestry with a virulence plasmid of Yersinia pestis. 相似文献
7.
The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design 总被引:1,自引:0,他引:1
Russell RJ Haire LF Stevens DJ Collins PJ Lin YP Blackburn GM Hay AJ Gamblin SJ Skehel JJ 《Nature》2006,443(7107):45-49
The worldwide spread of H5N1 avian influenza has raised concerns that this virus might acquire the ability to pass readily among humans and cause a pandemic. Two anti-influenza drugs currently being used to treat infected patients are oseltamivir (Tamiflu) and zanamivir (Relenza), both of which target the neuraminidase enzyme of the virus. Reports of the emergence of drug resistance make the development of new anti-influenza molecules a priority. Neuraminidases from influenza type A viruses form two genetically distinct groups: group-1 contains the N1 neuraminidase of the H5N1 avian virus and group-2 contains the N2 and N9 enzymes used for the structure-based design of current drugs. Here we show by X-ray crystallography that these two groups are structurally distinct. Group-1 neuraminidases contain a cavity adjacent to their active sites that closes on ligand binding. Our analysis suggests that it may be possible to exploit the size and location of the group-1 cavity to develop new anti-influenza drugs. 相似文献
8.
D E Humphries G W Wong D S Friend M F Gurish W T Qiu C Huang A H Sharpe R L Stevens 《Nature》1999,400(6746):769-772
9.
The motility of the gastrointestinal tract consists of local, non-propulsive mixing (pendular or segmental) and propulsive (peristaltic) movements. It is generally considered that mixing movements are produced by intrinsic pacemakers which generate rhythmic contractions, and peristalsis by intrinsic excitatory and inhibitory neural reflex pathways, but the relationship between mixing and peristalsis is poorly understood. Peristalsis is compromised in mice lacking interstitial cells of Cajal, suggesting that these pacemaker cells may also be involved in neural reflexes. Here we show that mixing movements within longitudinal muscle result from spontaneously generated waves of elevated internal calcium concentration which originate from discrete locations (pacing sites), spread with anisotropic conduction velocities in al directions, and terminate by colliding with each other or with adjacent neurally suppressed regions. Excitatory neural reflexes control the spread of excitability by inducing new pacing sites and enhancing the overall frequency of pacing, whereas inhibitory reflexes suppress the ability of calcium waves to propagate. We provide evidence that the enteric nervous system organizes mixing movements to generate peristalsis, linking the neural regulation of pacemakers to both types of gut motility. 相似文献
10.
We examined the distribution of Brechmorhoga mendax and B. pertinax (Libellulidae) in northern Arizona and southern Nevada. Brechmorhoga mendax occurs widely throughout the Southwest and in Arizona up to the Mogollon Rim, and up the Colorado River from the west to at least River Mile 132 (downstream from Lees Ferry, Arizona) at elevations of 110-1460 m. In Grand Canyon it occurs along small to large tributaries and on the mainstream at elevations below 650 m. The only previously reported locality for B. pertinax in the United States is in southeastern Arizona, where it was presumed to be accidental. We report B. pertinax along 5 small, perennial tributaries emanating from Redwall Formation aquifer springs on the south side of central Grand Canyon. Those springs habitats may be threatened by regional groundwater depletion. Brechmorhoga pertinax appears to be somewhat more stenotolerant in its habitat requirements than B. mendax , a finding in keeping with these differences in range. The presence of isolated populations of B. pertinax in Grand Canyon is an example of a Neotropical influence on the fauna and indicates biogeographic corridor and refuge functions of this large, deep canyon. 相似文献